Clinical and Safety Outcomes of Oral Antithrombotics for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Network Meta-analysis

Lin, Liang; Lim, Wee Shiong; Zhou, Hui; Khoo, Ai Leng; Tan, Keng Teng; Chew, Aik Phon; Foo, David; Chin, Jeffery; Lim, Boon Peng

doi:10.1016/j.jamda.2015.09.008

Cited by 41 publications

(68 citation statements)

References 62 publications

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“…Improved efficacy-safety profiles compared with warfarin of apixaban and other NOACs has been demonstrated recently in patients with nonvalvular atrial fibrillation in phase III clinical studies (Granger et al, 2011;Lin et al, 2015;Morais and De Caterina, 2016). The use of apixaban to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation was approved by the US Food and Drug Administration in 2012.…”

Section: Discussionmentioning

confidence: 99%

“…Since warfarin and the novel oral anticoagulants (NOACs) are the currently available options for stroke prevention in atrial fibrillation (Lin et al, 2015) and recent phase III clinical studies indicate that NOACs resulted in an overall better efficacy-safety profile than warfarin in patients with nonvalvular atrial fibrillation (Lin et al, 2015;Morais and De Caterina, 2016), we aimed to investigate the effects of apixaban as a representative example for the NOAC class on cerebral MES in our recently established preclinical model of cerebral MES. Apixaban was selected for this study because its in vitro and in vivo properties have been extensively characterized, along with efficacy assessment in various rabbit models of thrombosis and hemostasis for translational research (Pinto et al, 2007;Wong et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

Zhou

Chu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Cerebral microembolic signal (MES) is an independent predictor of stroke risk and prognosis. The objective of this study is to assess the effects of apixaban, as a representative of the novel oral anticoagulant class, on a rabbit model of cerebral MES. A clinical transcranial Doppler ultrasound instrument was used to assess MESs in the middle cerebral artery in a 30% FeCl 3 -induced carotid arterial thrombosis model in male New Zealand White rabbits. Ascending doses of apixaban were evaluated as monotherapy and in combination with aspirin on both arterial thrombosis and MES. Pharmacokinetic and pharmacodynamic responses were also evaluated. The effective dose for 50% inhibition (ED 50 ) of thrombus formation for monotherapy was 0.04 mg/kg per hour apixaban, i.v. (0.03 mM plasma exposure) for the integrated blood flow, 0.13 mg/kg per hour apixaban (0.10 mM plasma exposure) for thrombus weight, and 0.03 mg/kg per hour apixaban (0.02 mM plasma exposure) for MES. Dual treatment with aspirin (5 mg/kg, PO) and apixaban (0.015 mg/kg per hour, i.v.) resulted in a significant reduction in cerebral MES (P , 0.05) compared with monotherapy with either agent. Pharmacokinetic analysis of apixaban and pharmacodynamic assays using activated partial thromboplastin time (aPTT) and prothrombin time (PT) for apixaban-and arachidonic acidinduced platelet aggregation for aspirin were used to confirm the exposure-response relationships. In summary, our study demonstrates that apixaban in a concentration-dependent manner inhibits both arterial thrombosis and MES, suggesting a potential association between factor Xa (FXa) blockade and the reduction in MES in patients at risk of ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

Zhou

Chu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…However, management of VKA therapy is complicated due to the narrow therapeutic index, slow onset and offset of action, and numerous dietary and drug interactions. In recent years, a new class of non-VKA oral anticoagulants (NOACs; including direct thrombin receptor inhibitor dabigatran, and FXa inhibitors such as rivaroxaban and apixaban) were approved for SPAF based on their similar or superior benefit-risk profiles compared with warfarin (Granger et al, 2011;Lin et al, 2015;Morais and De Caterina, 2016). Nevertheless, NOACs are still associated with a significant bleeding risk.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Factor XIa Reduces the Frequency of Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

Wang¹,

Kurowski²,

Wu³

et al. 2016

J Pharmacol Exp Ther

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Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Because its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study used a potent and selective small molecule inhibitor of FXIa, compound 1, to assess the effect of FXI blockade in our recently established preclinical model of cerebral MES induced by FeCl 3 injury of the carotid artery in male New Zealand White rabbits. Ascending doses of compound 1 were evaluated simultaneously for both carotid arterial thrombosis by a Doppler flowmeter and MES in the middle cerebral artery by a transcranial Doppler. Plasma drug exposure and pharmacodynamic responses to compound 1 treatment were also assessed. The effective dose for 50% inhibition (ED 50 ) of thrombus formation was 0.003 mg/kg/h compound 1, i.v. for the integrated blood flow, 0.004 mg/kg/h for reduction in thrombus weight, and 0.106 mg/kg/h for prevention of MES. The highest dose, 3 mg/kg/h compound 1, achieved complete inhibition in both thrombus formation and MES. In addition, we assessed the potential bleeding liability of compound 1 (5 mg/kg/h, i.v., .1250-fold ED 50 levels in arterial thrombosis) in rabbits using a cuticle bleeding model, and observed about 2-fold (not statistically significant) prolongation in bleeding time. Our study demonstrates that compound 1 produced a robust and dose-dependent inhibition of both arterial thrombosis and MES, suggesting that FXIa blockade may represent a novel therapeutic strategy for the reduction in MES in patients at risk for ischemic stroke.

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“…The purpose of this study was to compare the clinical and safety outcomes of oral antithrombotics for stroke prevention in atrial fibrillation in younger (65 - 74 years) and older (≥ 75 years) elderly [9]. …”

Section: Reviewmentioning

confidence: 99%

“…Comparison between DOACs included dabigatran, 110 mg, dabigatran, 150 mg, rivaroxaban, apixaban, and edoxaban; however, this comparison demonstrated no difference in risk of SSE. Analysis of ischemic stroke included 16 RCTs (179,915 patient-years) and six NRSs (363,322 patient-years) [9]. In this analysis, DOACs exhibited an even smaller benefit for the outcome of ischemic stroke relative to SSE when compared to warfarin.…”

Section: Reviewmentioning

confidence: 99%

Efficacy and Safety of Direct Oral Anticoagulants Compared to Warfarin in Prevention of Thromboembolic Events Among Elderly Patients with Atrial Fibrillation

Kailas

Thambuluru

2016

Cureus

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Direct oral anticoagulants (DOACs), previously also known as novel oral anticoagulants (NOACs), have increased the therapeutic options for stroke prevention in atrial fibrillation (AF). Previous studies comparing their relative efficacy and safety do not address age-related differences, such as comorbidities and physical and social boundaries. This review aimed to summarize and compare the clinical and safety outcomes of DOACs and warfarin for stroke prevention in AF in the elderly population (≥ 65 years). We searched PubMed for randomized controlled trials and meta-analyses that compared DOACs and warfarin in elderly patients with AF. Stroke and systemic embolism (SSE) and major bleeding (MB) were primary outcomes. Secondary outcomes included ischemic stroke, all-cause mortality, intracranial bleeding, and gastrointestinal bleeding. Of 66 studies identified, one randomized control trial (RCT) and one meta-analysis were included. DOACs were at least as effective at reducing the risk of SSE as warfarin. DOACs demonstrated a minimal benefit for ischemic stroke (dabigatran, 110 mg, relative risk (RR) 1.08; edoxaban, 60 mg, RR 1.00; and apixaban, 5 mg, RR 0.99). DOACs associated with decreased risk of MB relative to warfarin include dabigatran, 110 mg; apixaban, 5 mg; and edoxaban, 60 mg (RR 0.80, 0.70, and 0.80, respectively), while dabigatran, 150 mg, and rivaroxaban, 20 mg, increased risk (RR 0.79 - 0.83, respectively). Dabigatran, 110 mg and 150 mg doses, and edoxaban increased the risk of gastrointestinal bleeding (RR 1.04, 1.12, and 1.23, respectively). Lower rates of SSE and intracranial bleeding were seen with DOACs compared to warfarin. Dabigatran, 150 mg, and rivaroxaban, 20 mg, were associated with higher MB in older elderly compared to warfarin. DOACs may be attractive alternatives to warfarin, but further studies are needed to make clinical recommendations.

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Clinical and Safety Outcomes of Oral Antithrombotics for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Network Meta-analysis

Cited by 41 publications

References 62 publications

Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

Inhibition of Factor XIa Reduces the Frequency of Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

Efficacy and Safety of Direct Oral Anticoagulants Compared to Warfarin in Prevention of Thromboembolic Events Among Elderly Patients with Atrial Fibrillation

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